Choline cocrystal of epalrestat

ABSTRACT

The invention relates to a novel choline cocrystal of 5-[(1Z.2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid. The preparation and characterization of the novel choline cocrystal according to various embodiments of the invention is described. The invention also relates to pharmaceutical compositions containing the novel choline cocrystal and the therapeutic use of the novel choline cocrystal to treat and/or prevent various conditions, including treating and/or preventing diabetic complications, treating and/or preventing homocystinuria reducing levels of homocysteine in blood serum, inhibiting aldose reductase, and affording cardioprotection in non-diabetic patients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/532,517,filed Nov. 4, 2014, which is a divisional of application Ser. No.13/062,644, filed Jul. 25, 2011, which is a national stage ofApplication No. PCT/US2009/55868, filed Sep. 3, 2009, and claimspriority under 35 U.S.C. § 119 to the benefit of U.S. ProvisionalApplication No. 61/094,904, filed Sep. 6, 2008, all of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The invention relates to a novel choline cocrystal of5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid, processes for making the novel cocrystal, pharmaceuticalcompositions comprising the novel choline cocrystal, and methods oftreating and/or preventing various conditions by administering the novelcholine cocrystal.

BACKGROUND

The compound5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid (shown below), referred to by its common name “epalrestat,” is aknown active pharmaceutical ingredient (“API”) having beneficialtherapeutic activity, for example as an aldose reductase inhibitor:

The preparation and pharmacologic activity of epalrestat is described inU.S. Pat. No. 4,831,045. Epalrestat is useful in treating and/orpreventing various conditions such as, for example, complications ofdiabetes, as well as affording cardioprotection in non-diabeticpatients. For example, epalrestat has a positive indication for thetreatment and/or prevention of diabetic neuropathy, and is useful forthe treatment and/or prevention of various other diabetic complicationsincluding, for example, diabetic retinopathy, diabetic nephropathy,diabetic cardiomyopathy, diabetic gastroparesis, diabeticmicroangiopathy, and diabetic microangiopathy in mammals. Epalrestat isalso useful in affording cardioprotection to subjects who may not besuffering from diabetes, and as a neuroprotectant or treatment forneurological or neurodegenerative disorders. Therapeutic activity ofepalrestat in various conditions has been demonstrated in the clinicalliterature, including but not limited to Machii H. et al., Gendai Iryo,1996; 28:1273; Miyamoto S. et al., Gendai Iryo, 1986; 18 (Extra IssueIII):82; Goto Y. et al., Journal of Clinical and Experimental Medicine,1990; 152:405; Nakano K. et al., Journal of Clinical and ExperimentalMedicine, 1990; 152:137; Okamoto H. et al., Internal Medicine, 2003;42:655-664; Hamada Y. et al., Diabetes Care 2000; 23:1539-44; Goto Y. etal., Diabet Med 1993; 10(suppl 2):S39-43; Goto Y. et al., BiomedPharmacother 1995; 49:269-77; Uchida K. et al., Clin Ther 1995;17:460-6; Hotta N. et al., J Diabetes Complications 1996; 10:168-72;Hotta N. et al., Diabetes Care 2006; 29:1538-44; Matsuoka K. et al.,Diabetes Res Clin Pract 2007; 77(suppl 1):S263-8; Nakayama M. et al.,Diabetes Care 2001; 24:1093-8; Baba M., Journal of the PeripheralNervous System 2003; 8:170; Yasuda H. et al., Diabetes Care 2000;23:705; Ikeda T et al., Diabetes Research and Clinical Practice 1999;43:193-198; Katayama M. et al., Electrocnccphalography and ClinicalNeurophysiology/Electromyography and Motor Control 1995; 97:81; andMisawa S. et al., Neurology 2006; 66:1545-9.

Although therapeutic efficacy is a primary concern for a therapeuticagent, such as epalrestat, the salt and solid state form (e.g.crystalline or amorphous forms) of a drug candidate can be important toits pharmacological properties and to its development as a viable API.For example, each salt or each solid form of a drug candidate can havedifferent solid state (physical and chemical) properties. Thedifferences in physical properties exhibited by a particular solid formof an API, such as a cocrystal, salt, or polymorph of the originalcompound, can affect pharmaceutical parameters of the API. For example,storage stability, compressibility and density, all of which can beimportant in formulation and product manufacturing, and solubility anddissolution rates, which may be important factors in determiningbioavailability, may be affected. Because these physical properties areoften influenced by the solid state form of the API, they cansignificantly impact a number of factors, including the selection of acompound as an API, the ultimate pharmaceutical dosage form, theoptimization of manufacturing processes, and absorption in the body.Moreover, finding the most adequate form for further drug developmentcan reduce the time and the cost of that development.

Obtaining pure crystalline forms, then, is extremely useful in drugdevelopment. It may permit better characterization of the drugcandidate's chemical and physical properties. For example, crystallineforms often have better chemical and physical properties than amorphousforms. As a further example, a crystalline form may possess morefavorable pharmacology than an amorphous form, or may be easier toprocess. It may also have better storage stability.

One such physical property which can affect processability is theflowability of the solid, before and after milling. Flowability affectsthe ease with which the material is handled during processing into apharmaceutical composition. When particles of the powdered compound donot flow past each other easily, a formulation specialist must take thatfact into account in developing a tablet or capsule formulation, whichmay necessitate the use of additional components such as glidants,including, for example, colloidal silicon dioxide, talc, starch, ortribasic calcium phosphate.

Another solid state property of a pharmaceutical compound that may beimportant is its dissolution rate in aqueous fluid. The rate ofdissolution of an active ingredient in a patient's stomach fluid mayhave therapeutic consequences since it can impact the rate at which anorally administered active ingredient may reach the patient'sbloodstream.

Another solid state property of a pharmaceutical compound that may beimportant is its thermal behavior, including its melting point. Themelting point of the solid form of a drug is optionally high enough toavoid melting or plastic deformation during standard processingoperations, as well as concretion of the drug by plastic deformation onstorage (See. e.g., Gould, P. L. Int. J. Pharmaceutics 1986 33 201-217).It may be desirable in some cases for a solid form to melt above about100° C. For example, melting point categories used by one pharmaceuticalcompany are, in order of preference, +(mp>120° C.), 0 (mp 80-120° C.),and −(mp<80° C.) (Balbach, S.; Korn, C. Int. J. Pharmaceutics 2004 2751-12).

Active drug molecules may be made into pharmaceutically acceptable saltsfor therapeutic administration to the patient. Crystalline salts of adrug may offer advantages over the free form of the compound, such asimproved solubility, stability, processing improvements, etc., anddifferent crystalline salt forms may offer greater or lesser advantagesover one another. However, crystalline salt formation is notpredictable, and in fact is not always possible. Moreover, there is noway to predict the properties of a particular crystalline salt of acompound until it is formed. As such, finding the right conditions toobtain a particular crystalline salt form of a compound, withpharmaceutically acceptable properties, can take significant time andeffort.

It is also possible to achieve desired properties of a particular API byforming a cocrystal of the API itself or of a salt of the API.Cocrystals are crystals that contain two or more non-identicalmolecules. Examples of cocrystals may be found in the CambridgeStructural Database. Examples of cocrystals may also be found at Etter,M. C., and Adsmond, D. A., J. Chem. Soc., Chem. Commun. 1990 589-591:Etter, M. C., MacDonald, J. C., and Bernstein, J., Acta Crystallogr.,Sect. B, Struct. Sci. 1990 B46 256-262; and Etter, M. C.,Urbaiczyk-Lipkowska, Z., Zia-Ebrahimi, M., and Panunto, T. W., J. Am.Chem. Soc. 1990 112 8415-8426, which are incorporated herein byreference in their entireties. The following articles are alsoincorporated herein by reference in their entireties: Görbotz C. H., andHersleth, H. P. Acta Cryst. 2000 B56 625-534; and Senthil Kumar, V. S.,Nangia, A., Katz, A. K., and Carrell, H. L., Crystal Growth & Design.2002 2 313-318.

By cocrystallizing an API or a salt of an API with a co-former (theother component of the cocrystal), one creates a new solid state form ofthe API which has unique properties compared with existing solid formsof the API or its salt. For example, a cocrystal may have differentdissolution and/or solubility properties than the active agent itself orits salt. Cocrystals containing APIs can be used to deliver APIstherapeutically. New drug formulations comprising cocrystals of APIswith pharmaceutically acceptable co-formers may, in some cases, havesuperior properties over existing drug formulations. However, cocrystalformation is not predictable, and in fact is not always possible.Moreover, there is no way to predict the properties of a particularcocrystal of a compound until it is formed. As such, finding the rightconditions to obtain a particular cocrystal of a compound, withpharmaceutically acceptable properties, can take significant time,effort, and resources.

A crystalline form of a compound, a crystalline salt of the compound, ora cocrystal containing the compound or its salt form generally possessesdistinct crystallographic and spectroscopic properties when compared toother crystalline forms having the same chemical composition.Crystallographic and spectroscopic properties of a particular form maybe measured by XRPD, single crystal X-ray crystallography, solid stateNMR spectroscopy, e.g. ¹³C CP/MAS NMR, or Raman spectrometry, amongother techniques. A particular crystalline form of a compound, of itssalt, or of a cocrystal, often also exhibits distinct thermal behavior.Thermal behavior can be measured in the laboratory by such techniquesas, for example, capillary melting point, TGA, and DSC.

In the following description, various aspects and embodiments of theinvention will become evident. In its broadest sense, the inventioncould be practiced without having one or more features of these aspectsand embodiments. Further, these aspects and embodiments are exemplary.Additional objects and advantages of the invention will be set forth inpart in the description which follows, and in part will be obvious fromthe description, or may be learned by practicing the invention. Theobjects and advantages of the invention will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims.

SUMMARY

In accordance with various embodiments of the invention and afterextensive experimentation, the inventors have discovered a novel cholinecocrystal of epalrestat, choline hydrogen diepalrestat.

The invention in various embodiments also relates to processes ofpreparing the novel choline cocrystal of epalrestat, pharmaceuticalcompositions containing the novel choline cocrystal of epalrestat, andits use in the treatment and/or prevention of various conditions such asdiabetic complications, and also to afford cardioprotection in patientswho may be non-diabetic.

As used herein, the term “XRPD” refers to x-ray powder diffraction. TheXRPD data disclosed herein were obtained using an Inel XRG-3000diffractometer equipped with a CPS (Curved Position Sensitive) detectorwith a 2θrange of 120°. Real time data were collected using Cu-Kαradiation at a resolution of 0.03° 2θ. The tube voltage and amperagewere set to 40 kV and 30 mA, respectively. The monochromator slit wasset at 5 mm by 160 μm. Samples were prepared for analysis by packingthem into thin-walled glass capillaries. Each capillary was mounted ontoa goniometer head that is motorized to permit spinning of the capillaryduring data acquisition. Instrument calibration was performed using asilicon reference standard.

As used herein, the term “DSC” refers to differential scanningcalorimetry. DSC data disclosed herein were obtained using a TAInstruments differential scanning calorimeter Q2000. The sample wasplaced into an aluminum DSC pan, and the weight accurately recorded. Thepan was crimped and the contents heated under nitrogen under theconditions given in the figures. Indium metal was used as thecalibration standard.

As used herein, the term “¹H-NMR” refers to proton nuclear magneticresonance spectroscopy. Solution ¹H NMR data disclosed herein wereacquired on a Varian ^(UNITY)INOVA-400 spectrometer (¹H LarmorFrequency=399.8 MHz). The specific parameters of each spectrum areprovided on the attached figures.

As shown below (Example 3), solubility data were collected in water atambient temperature over approximately 24 hours using an orbital shaker.Samples were taken at approximately 1, 3, 6, and 24 hours, and analyzedby UV spectrophotometry using a SpectraMax M2 UV-VIS spectrophotometer.Wavelength calibration and photometric accuracy were performed using theSpectraMax Pro 5 software as an internal calibration of the instrument.The detector was zeroed with a reference well on a microplate filledwith water on which data were obtained, and those data were subtractedfrom collected data. Samples were analyzed in the UV range at roomtemperature in the wells of a 96-well quartz plate.

As used herein with respect to the various analytical techniquesdescribed herein and data generated therefrom, the term “substantially”the same as or similar to is meant to convey that a particular set ofanalytical data is, within acceptable scientific limits, sufficientlysimilar to that disclosed herein such that one of skill in the art wouldappreciate that the form of the compound is the same as that of thepresent invention. One of skill in the art would appreciate that certainanalytical techniques, such as, for example, XRPD, ¹H-NMR, and DSC, willnot produce exactly the same results every time due to, for example,instrumental variation, sample preparation, scientific error, etc. Byway of example only, XRPD results (i.e. peak locations, intensities,and/or presence) may vary slightly from sample to sample, despite thefact that the samples are, within accepted scientific principles, thesame form, and this may be due to, for example, preferred orientation orvarying solvent or water content. It is well within the ability of thoseskilled in the art, looking at the data as a whole, to appreciatewhether such differences indicate a different form, and thus determinewhether analytical data being compared to those disclosed herein aresubstantially similar. In this regard, and as is commonly practicedwithin the scientific community, it is not intended that the exemplaryanalytical data of the novel choline hydrogen diepalrestat disclosedherein be met literally in order to determine whether comparative datarepresent the same form as that disclosed and claimed herein, such as,for example, whether each and every peak of the exemplary XRPD patterndisclosed herein is present in the comparative data, in the samelocation, and/or of the same intensity. Rather, as discussed above, itis intended that those of skill in the art, using accepted scientificprinciples, will make a determination based on the data as a wholeregarding whether comparative analytical data represent the same or adifferent form of the novel choline hydrogen diepalrestat disclosedherein.

As used herein, the terms “choline hydrogen diepalrestat” and “cholinehydrogen diacid cocrystal of epalrestat.” including variations which usethe chemical name“5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid” in place of the common name “epalrestat,” are used interchangeablyto refer to the novel choline cocrystal of epalrestat described herein.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an exemplary XRPD pattern of a choline hydrogen diacidcocrystal of epalrestat, according to one embodiment of the invention;

FIG. 2 is an exemplary DSC thermogram of a choline hydrogen diacidcocrystal of epalrestat, according to one embodiment of the invention;

FIG. 3A is an exemplary full ¹H-NMR spectrum of a choline hydrogendiacid cocrystal of epalrestat, according to one embodiment of theinvention;

FIG. 3B is an exemplary ¹H-NMR spectrum from 7.9 to 7.0 ppm of a cholinehydrogen diacid cocrystal of epalrestat, according to one embodiment ofthe invention;

FIG. 3C is an exemplary ¹H-NMR spectrum from 4.8 to 2.2 ppm of a cholinehydrogen diacid cocrystal of epalrestat, according to one embodiment ofthe invention;

FIG. 3D is an exemplary ¹H-NMR spectrum from 2.11 to 2.00 ppm of acholine hydrogen diacid cocrystal of epalrestat, according to oneembodiment of the invention;

FIG. 4 is an XRPD pattern of an intermediate product useful in anexemplary method of making a choline hydrogen diacid cocrystal ofepalrestat according to one embodiment of the invention;

FIG. 5A is a full ¹H-NMR spectrum of an intermediate product useful inan exemplary method of making a choline hydrogen diacid cocrystal ofepalrestat according to one embodiment of the invention;

FIG. 5B is an ¹H-NMR spectrum from 8.0 to 5.4 ppm of an intermediateproduct useful in an exemplary method of making a choline hydrogendiacid cocrystal of epalrestat according to one embodiment of theinvention;

FIG. 5C is an ¹H-NMR spectrum from 4.6 to 2.2 ppm of an intermediateproduct useful in an exemplary method of making a choline hydrogendiacid cocrystal of epalrestat according to one embodiment of theinvention; and

FIGS. 6A-6B show solubility data for a choline cocrystal of epalrestat,according to one exemplary embodiment of the invention.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

The invention relates to a novel choline cocrystal of epalrestat.Specifically, the novel cocrystal which has been discovered is a cholinehydrogen diacid cocrystal of epalrestat having two moles of epalrestatand one mole of choline. In one embodiment, the novel cocrystal isanhydrous. At least one exemplary method of preparation of the novelcholine cocrystal of epalrestat according to the invention is describedbelow in the examples.

The novel cocrystal described herein is obtained in a crystalline solidform, as seen by the high degree of crystallinity depicted in the XRPDpattern provided in FIG. 1. The cocrystal is shown to have distinctphysicochemical properties. The cocrystal of epalrestat described hereinis particularly suitable for the preparation of stable pharmaceuticalpreparations.

The novel choline cocrystal of epalrestat is characterized by an XRPDpattern substantially as shown in FIG. 1, a DSC thermogram substantiallyas shown in FIG. 2, an ¹H-NMR spectrum substantially as shown in FIGS.3A-3D, and a solubility profile substantially as shown in FIG. 6A. Anexemplary listing of representative XRPD peaks of the novel cholinecocrystal of epalrestat according to an embodiment of the invention canbe found in Table 1. An exemplary listing of representative NMR data canbe found in Table 2.

TABLE 1 °2θ d space (Å) Intensity (%)  6.1 ± 0.2 14.51 ± 0.48  100 12.4± 0.2 7.11 ± 0.11 47 12.7 ± 0.2 6.99 ± 0.11 41 13.3 ± 0.2 6.66 ± 0.10 3514.1 ± 0.2 6.28 ± 0.09 31 15.3 ± 0.2 5.80 ± 0.08 46 15.8 ± 0.2 5.60 ±0.07 16 16.6 ± 0.2 5.33 ± 0.06 17 17.2 ± 0.2 5.14 ± 0.06 50 18.2 ± 0.24.86 ± 0.05 13 18.8 ± 0.2 4.72 ± 0.05 19 20.0 ± 0.2 4.43 ± 0.04 13 20.2± 0.2 4.39 ± 0.04 9 21.3 ± 0.2 4.18 ± 0.04 72 21.6 ± 0.2 4.11 ± 0.04 7822.9 ± 0.2 3.89 ± 0.03 23 24.6 ± 0.2 3.62 ± 0.03 31 25.0 ± 0.2 3.56 ±0.03 50 25.8 ± 0.2 3.45 ± 0.03 67 27.0 ± 0.2 3.31 ± 0.02 37 28.4 ± 0.23.15 ± 0.02 9

TABLE 2 coupling peak constant number of protons position (ppm)multiplicity (Hz) protons impurity 2.06 multiplet — low intensityimpurity 2.09 singlet — low intensity CH₃ 2.22 doublet 0.9 3 CH₃(choline) 3.10 singlet — 4.5, partially obscured by water CH₂ (choline)3.38-3.40 multiplet — obscured by water CH₂ (choline) 3.81-3.85multiplet — 1 CH₂ 4.50 singlet — 2 olefin/aromatic 7.35-7.40 multiplet —2 olefin/aromatic 7.43-7.49 multiplet — 4 olefin 7.57 doublet 0.8 1Pharmaceutical Compositions and Methods of Treatment and/or Prevention

The novel choline cocrystal of epalrestat described herein possesses thesame general pharmacological activity as epalrestat free acid, and isuseful for treating and/or preventing diabetic complications such asthose discussed above, including, for example, diabetic neuropathy,diabetic retinopathy, and diabetic nephropathy. By use of the term“treating” or “alleviating” it is meant decreasing the symptoms,markers, or any negative effects of a condition in any appreciabledegree in a patient who currently has the condition, and by “preventing”it is meant preventing entirely or preventing to some extent, such as,for example, by delaying the onset or lessening the degree to which apatient develops the condition.

Accordingly, various embodiments of the invention include methods forpreventing and/or treating cardiac tissue ischemia in a mammalcomprising administering to said mammal an effective amount of a novelcholine cocrystal of epalrestat as described herein. Various embodimentsof the invention also include methods for treating and/or preventingcardiac tissue ischemia in a mammal comprising administering to saidmammal a pharmaceutical composition comprising a novel choline cocrystalof epalrestat and a pharmaceutically acceptable vehicle, carrier, and/ordiluent. In exemplary methods, said mammal may be suffering from cardiactissue ischemia or may be at risk of suffering from cardiac tissueischemia. For example, a mammal at risk may be awaiting or undergoingcardiac, cardiovascular, or other major surgery. Thus, variousembodiments of the invention include methods for providing myocardialprotection during surgery or myocardial protection in patientspresenting with ongoing cardiac or cerebral ischemic events or chroniccardioprotection in patients diagnosed with, or at risk for, coronaryheart disease, cardiac dysfunction or myocardial stunning. As usedherein, “mammal” is intended to include humans.

Various embodiments of the invention include methods of inhibitingaldose reductase in a mammal in need of inhibition of aldose reductasecomprising administering an aldose reductase inhibiting amount of anovel choline cocrystal of epalrestat as described herein. Variousembodiments of the invention also include methods of inhibiting aldosereductase in a mammal in need of inhibition of aldose reductasecomprising administering a pharmaceutical composition comprising a novelcholine cocrystal of epalrestat as described herein, and apharmaceutically acceptable vehicle, carrier, and/or diluent.

Additional embodiments of the invention include methods of treatingand/or preventing one or more diabetic complications in a mammalsuffering from one or more diabetic complications comprisingadministering to said mammal an effective amount of a novel cholinecocrystal of epalrestat as described herein. Diabetic complicationswhich may be treated and/or prevented by exemplary methods of theinvention include, but are not limited to, diabetic neuropathy, diabeticnephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabeticgastroparesis, cataracts, foot ulcers, diabetic macroangiopathy, anddiabetic microangiopathy. Various embodiments of the invention are alsodirected to methods of treating and/or preventing one or more diabeticcomplications in a mammal suffering from one or more diabeticcomplications comprising administering to said mammal an effectiveamount of a pharmaceutical composition as set forth herein.

Further embodiments of the invention contemplate methods of treatingand/or preventing homocystinuria, and/or reducing levels of homocysteinein the blood serum, for example in a patient with diabetes, byadministering an effective amount of a novel choline cocrystal ofepalrestat, or composition and/or formulation comprising an effectiveamount of a novel choline cocrystal of epalrestat, as described herein.In vivo, choline is converted to betaine, also known as trimethylglycineor glycine betaine. Both choline and betaine are naturally occurringmolecules found in dietary sources (Olthof M R, Curr Drug Metab 2005;6:15-22). In biological systems, betaine is important in the metabolismof homocysteine, and functions as a methyl donor. Betaine is thereforeused therapeutically to reduce elevated homocysteine concentrations (vanGuldener C et al, Expert Opinion on Pharmacotherapy 2001; 2:1449-1460),and is approved for use in the U.S. and Europe as a therapeutic agent totreat homocystinuria from genetic causes (Cystadane prescribinginformation, FDA; Cystadane product information, EMEA). In animalstudies, dietary choline deprivation has also been shown to lead toelevated homocysteinc (Setoue M et al, J Nutr Sci Vitaminol 2008;54:483-90), and choline supplementation has been shown to reduceelevated homocysteine levels (Setoue M et al, Biosci Biotechnol Biochem2008; 72:1696-703). In humans, epidemiologic studies have shown thegeneral population to have dietary choline intake levels below therecommended adequate intake level (Bidulescu A et al, Nutr J 2009;8:14), and in pilot studies, choline supplementation has loweredelevated homocysteine levels (Olthof M R et al, Am J Clin Nutr 2005;82:111-7). Elevated homocysteine is associated with cardiovasculardisease in both Type 2 diabetes (Hoogeveen E K et al, ArteriosclerThromb Vasc Biol 1998; 18:133-138) and in non-diabetic populations(Bostom A G et al, Arch Intern Med 1999; 159:1077-1080). Homocysteine isalso elevated in patients with various non-cardiovascular diabeticcomplications, including diabetic nephropathy (Bostom A G et al,Arterioscler Thromb Vasc Biol 1997; 17:2554-2558), diabetic rctinopathy(Brazionis L et al, Diabetes Care 2008; 31:50-56), and diabeticneuropathy (Ambrosch A et al, Diabetic Medicine 2001; 18:185-192).Administration of a novel choline cocrystal of epalrestat may thereforehave an additional beneficial therapeutic effect for treating theseconditions.

Various additional embodiments of the invention include methods ofpalliating neurological disorders and delaying development ofneurological disorders using aldose reductase inhibitors, in order tomodulate neurotrophic factor-associated activity, especiallyCNTF-associated levels and activity, for example as disclosed in U.S.Pat. No. 6,696,407. These methods are useful, for example, for acondition or circumstance in which neurotrophic factor-associatedactivity is indicated, such as neurological disorders, includingneurodegenerative disorders. A “neurological disorder” as used hereinmeans an aberration from clinically normal neural cell activity (i.e.,compromised neural cell activity) and includes, by way of example only,neurodegenerative disease (of the CNS and/or PNS), neuropathiesassociated with toxicity (neurotoxicity) such as chemotherapy (i.e.,vincristine or cisplatin-induced motor neuropathy) and alcoholconsumption, immune-mediated neurodiseases such as multiple sclerosis(MS) and Guillain-Barre syndrome, hereditary neuropathies such asCharcot-Marie-Tooth neuropathies [see Lebo et al. (1992) Am. J. Hum.Genet. 50:42-55], injury due to trauma, and compromised function due tosenescence. Examples of neurodegenerative disorders include but are notlimited to, Huntington's disease, amyotrophic lateral sclerosis (ALS),Alzheimer's disease, Parkinson's disease, and Shy-Drager syndrome. Themethods may also be useful in delaying development of a neurologicaldisorder, and thus may be used in individuals who show no overt signs ofdisease but are, for example, at risk of developing disease.

As discussed, additional embodiments of the invention relate topharmaceutical compositions comprising any amount, such as atherapeutically effective amount, of a novel choline cocrystal ofepalrestat as described herein and a pharmaceutically acceptable carrieror excipient. The novel choline cocrystal of epalrestat according to theinvention has the same or similar pharmaceutical activity as previouslyreported for epalrestat free acid. Pharmaceutical compositions for thetreatment and/or prevention of those conditions or disorders may containsome amount, for example a therapeutically effective amount, of a novelcholine cocrystal of epalrestat described herein, as appropriate. e.g.for treatment of a patient with the particular condition or disorder. Asa further example, the amount of the cocrystal in the pharmaceuticalcompositions may likewise be lower than a therapeutically effectiveamount, and may, for example, be in the composition in conjunction withanother compound or form of epalrestat which, when combined, are presentin a therapeutically effective amount. A “therapeutically effectiveamount” as described herein refers to an amount of a therapeutic agentsufficient to treat, alleviate, and/or prevent a condition treatableand/or preventable by administration of a composition of the invention,in any degree. That amount can be an amount sufficient to exhibit adetectable therapeutic or preventative or ameliorative effect, and canbe determined by routine experimentation by those of skill in the art.The effect may include, for example, treatment, alleviation, and/orprevention of the conditions listed herein. The actual amount required,e.g. for treatment of any particular patient, will depend upon a varietyof factors including the disorder being treated and/or prevented; itsseverity; the specific pharmaceutical composition employed; the age,body weight, general health, gender, and diet of the patient; the modeof administration; the time of administration; the route ofadministration; the rate of excretion of epalrestat; the duration of thetreatment; any drugs used in combination or coincidental with thespecific compound employed; and other such factors well known in themedical arts. These factors are discussed in Goodman and Gilman's “ThePharmacological Basis of Therapeutics”, Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001.

A pharmaceutical composition according to various embodiments of theinvention may be any pharmaceutical form which contains a novel cholinecocrystal of epalrestat as described herein. Depending on the type ofpharmaceutical composition, the pharmaceutically acceptable carrier maybe chosen from any one or a combination of carriers known in the art.The choice of the pharmaceutically acceptable carrier depends upon thepharmaceutical form and the desired method of administration to be used.For a pharmaceutical composition according to various embodiments of theinvention, that is one having a novel choline cocrystal of epalrestat asdescribed herein, a carrier may be chosen that maintains the cocrystalform. In other words, the carrier, in some embodiments, will notsubstantially alter the cocrystal form of epalrestat as describedherein. In some embodiments, the carrier will similarly not be otherwiseincompatible with epalrestat itself, such as by producing anyundesirable biological effect or otherwise interacting in a deleteriousmanner with any other component(s) of the pharmaceutical composition.

The pharmaceutical compositions according to various embodiments of theinvention are optionally formulated in unit dosage form for ease ofadministration and uniformity of dosage. A “unit dosage form” refers toa physically discrete unit of therapeutic agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily dosage of a novel choline cocrystal of epalrestat described hereinand pharmaceutical compositions thereof will be decided by the attendingphysician within the scope of sound medical judgment using knownmethods.

Because the novel choline cocrystal of epalrestat as described herein ismore easily maintained during preparation, solid dosage forms are apreferred form for the pharmaceutical composition of the invention.Solid dosage forms for oral administration may include, for example,capsules, tablets, pills, powders, and granules. In one exemplaryembodiment, the solid dosage form is a tablet. The active ingredient maybe contained in a solid dosage form formulation that provides quickrelease, sustained release, or delayed release after administration tothe patient. In such solid dosage forms, the active compound may bemixed with at least one inert, pharmaceutically acceptable carrier, suchas, for example, sodium citrate or dicalcium phosphate. The solid dosageform may also include one or more of various additional ingredients,including, for example: a) fillers or extenders such as, for example,starches, lactose, sucrose, glucose, mannitol, and silicic acid; b)binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants suchas, for example, glycerol; d) disintegrating agents such as, forexample, agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate; e) dissolution retardingagents such as, for example, paraffin; f) absorption accelerators suchas, for example, quaternary ammonium compounds; g) wetting agents suchas, for example, cetyl alcohol and glycerol monostearate; h) absorbentssuch as, for example, kaolin and bentonite clay; and i) lubricants suchas, for example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, and sodium lauryl sulfate. The solid dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutical compositions and known techniques for thepreparation thereof. Solid dosage forms of pharmaceutical compositionsaccording to various embodiments of the invention can also be preparedwith coatings and shells such as enteric coatings and other coatingswell known in the pharmaceutical formulating art.

The novel choline cocrystal of epalrestat described herein can be, inone exemplary embodiment, administered in a solid micro-encapsulatedform with one or more carriers as discussed above. Microencapsulatedforms may also be used in soft and hard-filled gelatin capsules withcarriers such as lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

The novel choline cocrystal of epalrestat as described herein may alsobe used in the preparation of non-solid formulations, e.g., injectablesand patches, of epalrestat. Such non-solid formulations are known in theart. In a non-solid formulation, the cocrystal form may, in certainexemplary embodiments, not be maintained. For example, the cocrystal maybe dissolved in a liquid carrier. In this case, the novel cocrystal ofepalrestat described herein may represent intermediate forms ofepalrestat used in the preparation of the non-solid formulation. Thenovel choline cocrystal of epalrestat described herein may provideadvantages of handling stability and purity to the process of makingsuch formulations.

The invention also relates to the treatment and/or prevention ofdiabetes-associated disorders such as those discussed above. Theinvention provides a method for treating and/or preventingdiabetes-associated disorders by administering to mammals a novelcholine cocrystal of epalrestat as described herein, or a pharmaceuticalcomposition containing the same, in an amount sufficient to treat and/orprevent a condition treatable and/or preventable by administration of acomposition of the invention. That amount is the amount sufficient toexhibit any detectable therapeutic and/or preventative or ameliorativeeffect. The effect may include, for example, treatment and/or preventionof the conditions listed herein. The novel choline cocrystal ofepalrestat and pharmaceutical compositions containing the same may,according to various embodiments of the invention, be administered usingany amount, any form of pharmaceutical composition, and any route ofadministration effective, e.g. for treatment, all of which are easilydetermined by those of skill in the art through routine experimentation.After formulation with an appropriate pharmaceutically acceptablecarrier in a desired dosage, as known by those of skill in the art, thepharmaceutical compositions can be administered to humans and othermammals by any known method, such as, for example, orally, rectally, ortopically (such as by powders or other solid form-based topicalformulations). In certain embodiments, the novel choline cocrystal ofepalrestat according to the invention may be administered at dosagelevels ranging from about 0.001 mg/kg to about 50 mg/kg, from about 0.01mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect. It will also be appreciated that dosagessmaller than about 0.001 mg/kg or greater than about 50 mg/kg (forexample, ranging from about 50 mg/kg to about 100 mg/kg) can also beadministered to a subject in certain embodiments of the invention. Asdiscussed above, the amount required for a particular patient willdepend upon a variety of factors including the disorder being treatedand/or prevented; its severity; the specific pharmaceutical compositionemployed; the age, body weight, general health, gender, and diet of thepatient; the mode of administration; the time of administration; theroute of administration; the rate of excretion of epalrestat; theduration of the treatment; any drugs used in combination or coincidentalwith the specific compound employed; and other such factors well knownin the medical arts. And, as also discussed, the pharmaceuticalcompositions comprising a novel choline cocrystal of epalrestat asdescribed herein may be administered as a unit dosage form.

Although the present invention herein has been described with referenceto various exemplary embodiments, it is to be understood that theseembodiments are merely illustrative of the principles and applicationsof the present invention. Those having skill in the art would recognizethat a variety of modifications to the exemplary embodiments may bemade, without departing from the scope of the invention.

Moreover, it should be understood that various features and/orcharacteristics of differing embodiments herein may be combined with oneanother. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments and that other arrangementsmay be devised without departing from the scope of the invention.

Furthermore, other embodiments of the invention will be apparent tothose skilled in the art from consideration of the specification andpractice of the invention disclosed herein. It is intended that thespecification and examples be considered as exemplary only, with a scopeand spirit being indicated by the claims.

EXAMPLES Example 1—Preparation of the Intermediate Product

A slurry of 265 mg (0.83 mmol) of epalrestat free acid and 20 mL ofabsolute ethanol was treated with 0.187 mL of 50% aqueous cholinehydroxide (0.187 mL with a density of 1.073 g/mL-201 mg 50% cholinehydroxide by weight=101 mg, 0.83 mmol of choline hydroxide). During theaddition, all of the solid dissolved. The resulting solution was pouredinto 400 mL of diethyl ether and the precipitated solids were collectedby filtration to give 282 mg of product. The solids were dried in avacuum oven at 1-5 torr pressure and ambient temperature overnight. Thesolids were collected and analytical data were obtained on theintermediate product: the XRPD pattern was as shown in FIG. 4, and the¹H-NMR spectrum was as shown in FIGS. 5A-5C.

Example 2—Preparation of a Choline Hydrogen Diacid Cocrystal ofEpalrestat

A mixture of 209 mg of epalrestat free acid and II mL acetone wassonicated briefly and filtered through a 0.2 micron nylon filter. Thefiltrate was treated with 39 mg of the intermediate product of Example 1to give a slurry. The slurry was agitated by placing it in a capped vialon a rotating wheel for about 4 days. Filtration afforded 56 mg of solidcholine hydrogen diepalrestat. Analytical data were obtained on theproduct: the XRPD pattern is shown in FIG. 1, the DSC thermogram isshown in FIG. 2, and the ¹H-NMR spectrum is shown in FIGS. 3A-3D.Elemental analysis was as follows:

% C % H % N % S Experimental (1B) 54.13 4.48 5.40 17.11 Theoretical56.66 5.30 5.66 17.29

Example 3—Preparation of a Choline Hydrogen Diacid Cocrystal ofEpalrestat

A mixture of 85 mg of epalrestat free acid and 20 mL of absolute ethanolwas briefly sonicated and filtered through a 0.2 micron nylon filter.The filtrate was treated with 26 mg of the intermediate product ofExample 1 with sonication to give a slurry. The slurry was agitated byplacing it in a capped vial on a rotating wheel for about 4 days.Filtration afforded 36 mg of solid choline hydrogen diepalrestat.Analytical data were obtained on the product: the XRPD pattern wassubstantially as shown in FIG. 1. Solubility data were obtained in wateron the final product, and the solubility profile is shown in FIG. 6A. Ascan be seen in FIG. 6A, the dissolved concentration of epalrestatincreased over time to 249 μg/mL after approximately 24 hours. As can beseen in FIG. 6B, the choline hydrogen diacid cocrystal of epalrestatappears to have a greater solubility in water than the free acid.

What is claimed is:
 1. A method of treating any of the followingconditions comprising administering a pharmaceutical compositioncomprising a choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid having an XRPD pattern substantially similar to that in FIG. 1:diabetic nephropathy, diabetic cardiomyopathy, or diabetic retinopathy.2. A method of delaying the onset of, or lessening the degree to which apatient develops, any of the following conditions comprisingadministering a pharmaceutical composition comprising a choline hydrogendiacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid having an XRPD pattern substantially similar to that in FIG. 1:cardiac tissue ischemia, diabetic neuropathy, diabetic nephropathy,diabetic cardiomyopathy, diabetic retinopathy, diabetic gastroparesis,cataracts, foot ulcers, diabetic macroangiopathy, and diabeticmicroangiopathy.
 3. The method according to claim 1, wherein thepharmaceutical composition comprises an amount of the choline hydrogendiacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid effective to treat said condition.
 4. The method according to claim1, wherein the pharmaceutical composition comprises an amount of thecholine hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid less than the amount effective to treat said condition, and whereinthe pharmaceutical composition further comprises at least one additionalcompound or form of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid which, when combined with the choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid, provides a combined effective amount for treating said condition.5. The method according to claim 1, wherein the pharmaceuticalcomposition further comprises a pharmaceutically acceptable carrierand/or excipient.
 6. The method according to claim 1, wherein thepharmaceutical composition is suitable for preserving the cocrystal formof the choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid.
 7. The method according to claim 1, wherein the pharmaceuticalcomposition comprises an amount of the choline hydrogen diacid cocrystalof5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid to provide a dosage ranging from about 0.001 mg/kg to about 50mg/kg per day.
 8. The method according to claim 1, wherein thepharmaceutical composition is administered once daily.
 9. The methodaccording to claim 1, wherein the pharmaceutical composition isadministered two or more times per day.
 10. The method according toclaim 2, wherein the pharmaceutical composition comprises an amount ofthe choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid effective to delay the onset of, or lessen the degree to which apatient develops, said condition.
 11. The method according to claim 2,wherein the pharmaceutical composition comprises an amount of thecholine hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid less than the amount effective to delay the onset of, or lessen thedegree to which a patient develops, said condition, and wherein thepharmaceutical composition further comprises at least one additionalcompound or form of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid which, when combined with the choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid, provides a combined effective amount for delaying the onset of, orlessening the degree to which a patient develops, said condition. 12.The method according to claim 2, wherein the pharmaceutical compositionfurther comprises a pharmaceutically acceptable carrier and/orexcipient.
 13. The method according to claim 2, wherein thepharmaceutical composition is suitable for preserving the cocrystal formof the choline hydrogen diacid cocrystal of5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid.
 14. The method according to claim 2, wherein the pharmaceuticalcomposition comprises an amount of the choline hydrogen diacid cocrystalof5[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineaceticacid to provide a dosage ranging from about 0.001 mg/kg to about 50mg/kg per day.
 15. The method according to claim 2, wherein thepharmaceutical composition is administered once daily.
 16. The methodaccording to claim 2, wherein the pharmaceutical composition isadministered two or more times per day.